p53 is a house-keeping protein, the activity and expression of which, as well as its cellular pathway, are critically implied in the maintaining of cell homeostasis, and the occurrence of numerous diseases. Indeed, numerous diseases may result from a deregulation of p53, either in its expression, or in its activity or cellular pathway, including its activating factors or its target genes.
The p53 gene is the most frequently mutated gene in cancers. Its tumour suppressor activity relies on its ability to control proliferation by inducing apoptosis, cell cycle arrest and senescence in response to cellular stresses, such as DNA damages. Almost all human cancer exhibit defects in p53 activation either by p53 gene mutation which occurs in around 50% of human cancers, or by the failure (shortcoming) of the pathways promoting its activation.
The p53 pathway is also implicated in other diseases such as inflammation, fibrosis, neurodegenerative diseases, ischemia, atherosclerosis, pathogenesis of a number of hepatic disorders, such as cholestasis, autoimmune diseases, ethanol-induced injuries such as alcoholic liver diseases (ALD) including fatty liver, alcoholic hepatitis and cirrhosis, ribosome biogenesis disorders such as Treacher Collins syndrome (TCS), male infertility, alopecia, neurological defects, endocrinopathy syndrome (ANE syndrome), Shwachman-Diamond syndrome (SDS) and neurofibromatosis type 1 (NF1), and HIV-associated pathologies such as dementia, diabetes and myocardial infarction.
Indeed, in diseases other than cancer, the inhibition of wild-type p53 may represent a new therapeutic strategy. Thus, inhibition of p53 activity or cellular pathway might be highly beneficial in the prevention of injury to diverse organs (Georgiev et al., Curr Pharm Des, 2006 12:2911), or in treatment of myocardial infarction (Matsusaka et al., 2006). Also, ischemia, or diseases associated with neurodegenerative pathological conditions, including AIDS-associated neurodegeneration, stroke, Parkinson's, Alzheimer's, and Huntington's diseases (Vousden & Lane, 2007, Nat Rev Mol Cell Biol. 2007 April; 8(4):275-83), clinical management of hepatic disease induced by toxic bile salts (Oh et al., 2002 Toxicol Appl Pharmacol. 2002 Jul. 1; 182(1):27-33), or atherosclerosis in which wild-type p53 is over-expressed (Iacopetta et al., Int J Oncol, 1995, 7, 399-402), may benefit from compounds able to curb deregulated p53.
Document WO2009/087238 discloses compounds effective in treating diseases related to the splicing process.
Up to now, to the knowledge of the inventors, no drug repressing mutated p53 expression has been described. Indeed activation of p53 pathway is generally obtained but no reduction of p53 pathway.
Therefore, there is an existing need to find out compounds able to compensate deregulated p53 expression, activity, or cellular pathway.
More particularly, there is a need to identify new compounds able to inhibit or reduce the expression of mutated p53 isoforms, preferably without affecting the expression of wild-type p53 isoforms.
There is a need to have compounds able to favour the expression of non-mutated p53 isoforms over mutated p53 isoforms.
There is also a need to have compounds able to modulate the p53 gene expression, and in particular able to specifically modulate the splicing of p53 isoforms.
There is also a need to have compounds able to prevent or reduce over expression of wild-type isoform(s) of p53.
There is also a need to have compounds able to prevent or increase low-expression of wild-type isoform(s) of p53.
More precisely, there is a need to find out compounds able to prevent, inhibit and/or treat a disease in a patient suffering thereof, said disease involving deregulated p53.
More particularly, there is a need to have compounds able to prevent, inhibit and/or treat a disease in a patient suffering thereof, said disease involving mutated p53, and/or deregulated wild-type p53.
More particularly, there is a need to have compounds able to prevent, inhibit and/or treat a cancer in a patient suffering thereof, said cancer involving a mutated p53 or deregulated wild-type p53, such as a low-expression of wild-type p53.
There is a need to have compounds able to prevent, inhibit and/or treat atherosclerosis in a patient suffering thereof, said atherosclerosis involving a mutated p53, or a deregulated wild-type isoform of p53, such as a low-expression of wild-type p53.
There is also a need to have compounds able to prevent, inhibit and/or treat a disease in a patient suffering thereof, said disease involving a deregulated wild-type p53, such as a disease chosen from inflammation, fibrosis, neurodegenerative diseases, ischemia, atherosclerosis, hepatic disorders, such as cholestasis, autoimmune diseases, and ethanol-induced injuries such as alcoholic liver diseases (ALD) including fatty liver, alcoholic hepatitis and cirrhosis, ribosome biogenesis disorders such as Treacher Collins syndrome (TCS), male infertility, alopecia, neurological defects, endocrinopathy syndrome (ANE syndrome), Shwachman-Diamond syndrome (SDS) and neurofibromatosis type 1 (NF1), and HIV-associated pathologies such as dementia, diabetes and myocardial infarction.